Mr. Min Koon Koek
Lot 4, Gate A, Jalan Teknologi 3/6, Seksyn 3
Taman Sains Selangor
47810 Petaling Jaya
Warning Letter 320-24-09
November 17, 2023
Dear Mr. Min Koon Koek:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, AmLion Toothpaste Mfg. Sdn. Bhd., FEI 3006057298, at Lot 4, Gate A, Jalan Teknologi 3/6, Seksyn 3, Taman Sains Selangor, Petaling Jaya, Selangor, from July 10 to 14, 2023.
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
We reviewed your August 8, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).
You manufacture over-the-counter (OTC) drug products including toothpaste for children. You failed to adequately test your incoming components for identity before using the components to manufacture your OTC drug products. You also failed to adequately qualify your suppliers, as you have not validated the test results of your suppliers’ analyses, but instead, you relied on your suppliers’ responses to your vendor questionnaire. Your quality unit (QU) does not approve these questionnaires, but instead, your purchasing personnel performs the review, and your General Manager approves the suppliers. By not analyzing your components for identity, purity, strength, and quality, you failed to ensure that your incoming components meet appropriate specifications.
Furthermore, you failed to adequately test your incoming components at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination for identity before using them to manufacture your drug products. These include, but are not limited to, testing of glycerin and sorbitol solution you used in manufacturing your drug products to determine their appropriate identity. Identity testing for these and certain other high-risk drug components include a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the manufacture of your drug products.
The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.
In your response, you commit to improving your component controls. However, your response is inadequate because you did not provide supportive documentation, lacked a retrospective impact assessment, and your interim production plans are unclear.
In response to this letter, provide:
- A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of your drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of DEG and EG.
- A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including, but not limited to, glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective action and preventive action (CAPA) that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
- A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s certificate of analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.
- The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
- A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
2. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
Your QU lacked adequate oversight for the manufacture of your drug product. For example, you lacked adequate procedures describing the roles and responsibilities of the QU. Your In-Process Quality Control (IPQC) staff are able to review and approve manufacturing documentation, including batch production records, without further review or oversight by your QU. According to your organizational structure, your IPQC staff reports directly to your general managers and not the QU. Additionally, you failed to conduct adequate investigations of deviations observed during manufacturing and when our investigator asked if unplanned deviations were documented, you replied that they were not.
In your response, you commit to expanding the roles and responsibilities of your QU. However, your response is inadequate because you did not provide supportive documentation and your completion timelines are unclear.
In response to this letter, provide:
- A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
o A complete and final review of each batch and its related information before the QU disposition decision
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
You failed to establish and follow an adequate written stability program to determine appropriate storage conditions and expiration dates of drug products manufactured at your facility. For example, your stability program lacked appropriate testing of your drug products, including testing of active ingredients, impurities, and other degradation products. Additionally, stability samples are stored inside a room that lacks temperature and humidity controls.
Without appropriate stability studies, you lack scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their expiry.
In your response, you commit to establishing a new stability protocol. Your response is inadequate because you did not provide supportive documentation, it lacks a retrospective impact assessment, it lacks completion timelines, and your interim production plans are unclear.
In response to this letter, provide:
- A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
o Stability indicating methods
o Stability studies for each drug product in its marketed container-closure system before distribution is permitted
o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid
o Detailed definition of the specific attributes to be tested at each station (timepoint)
o All procedures that describe these and other elements of your remediated stability program
4. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
You failed to adequately validate your manufacturing processes for your OTC drug products. Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing of throughout each significant process stage to characterize intra-batch variation and evaluates batches to determine whether an initial state of control has been established.
Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.
See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.
Furthermore, maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a process remains in control. For example, investigators observed white residue and what appears to be rust on product contact surfaces of your production equipment labeled as clean.
In your response, you commit to completing process validation activities by October 2023. However, you likewise committed to completing process validation activities following the 2015 and 2018 inspections. Your response is inadequate because you did not provide supportive documentation, it lacks a retrospective impact assessment, and your interim production plans are unclear.
In response to this letter, provide:
- A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
- A timeline for performing appropriate PPQ for each of your marketed drug products.
- Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
- Provide a detailed program for designing, validating, maintaining, controlling, and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
Repeat Observations at Facility
In previous inspections ending on June 4, 2015, and March 2, 2018, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
CGMP Consultant Recommended
Because you failed to correct repeat violations, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit1 of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
FDA placed your firm on Import Alert 66-40 on August 18, 2023, after your response to our 704(a)(4) Request for Records sent to you on March 22, 2023, demonstrated CGMP violations related to controls for DEG/EG in high-risk components used in your drugs. The inspectional findings detailed above further demonstrate your firm’s noncompliance.
Your firm remains on Import Alert 66-40.
Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.
Failure to address any violation may also result in the FDA continuing to refuse admission of articles manufactured at AmLion Toothpaste Mfg. Sdn. Bhd. at Lot 4, Gate A, Jalan Teknologi 3/6, Seksyn 3, Taman Sains Selangor, Petaling Jaya, Selangor, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Send your electronic reply to [email protected]. Identify your response with FEI 3006057298 and ATTN: Kevin Maguire.
Identify your response with FEI 3006057298.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
1 i.e., Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.